Alpha synuclein-mediated cytoskeletal dysfunction impairs myelination in human oligodendrocytes

IF 9.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2025-09-19 DOI:10.1007/s00401-025-02933-z

Jeanette Wihan, Kristina Battis, Alana Hoffmann, Farina Windener, Marcus Himmler, Anish Varghese, Aron Koller, Isabell Karnatz, Dirk W. Schubert, Friederike Zunke, Wei Xiang, Tanja Kuhlmann, Jürgen Winkler

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引用次数: 0

Abstract

Oligodendroglial alpha-synuclein (aSyn) deposits are a key feature in the atypical parkinsonian disorder, multiple system atrophy (MSA) linked to profound myelin loss and neurodegeneration while precise cellular and molecular mechanisms remain unclear. We generated human oligodendrocytes (hOLs) from induced pluripotent stem cells to investigate the impact of aSyn on oligodendroglial morphology, differentiation, and function. We observed an aSyn-induced myelinogenic dysfunction characterized by impaired oligodendroglial process outgrowth, altered cell shape, and increased perinuclear accumulation of the tubulin polymerization promoting protein TPPP/p25α. These changes were associated with a reduced capacity to ensheath axons and were linked to compromised actin remodeling machinery. Actin imbalances were confirmed in post-mortem putaminal tissue from MSA patients. Treatment with a rho-associated protein kinase inhibitor rescued oligodendroglial process formation and improved ensheathment in aSyn-expressing hOLs. Our work emphasizes the aSyn-mediated interference with actin dynamics as a key pathogenic mechanism in MSA, pointing toward a novel therapeutic target for improving myelin maintenance.

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α突触核蛋白介导的细胞骨骼功能障碍损害人少突胶质细胞的髓鞘形成。

少突胶质α -突触核蛋白（aSyn）沉积是非典型帕金森病、多系统萎缩（MSA）的一个关键特征，与髓磷脂严重丢失和神经退行性变有关，但精确的细胞和分子机制尚不清楚。我们从诱导多能干细胞中生成人少突胶质细胞（hOLs），以研究aSyn对少突胶质细胞形态、分化和功能的影响。我们观察到一种以少突胶质生长受损、细胞形状改变和核周微管蛋白聚合促进蛋白TPPP/p25α积累增加为特征的非async诱导髓鞘生成功能障碍。这些变化与包膜轴突的能力降低有关，并与肌动蛋白重塑机制受损有关。肌动蛋白失衡在MSA患者死后的壳层组织中得到证实。用rho相关蛋白激酶抑制剂治疗可挽救表达异步的hOLs的少突胶质过程形成并改善鞘层。我们的工作强调了异步介导的对肌动蛋白动力学的干扰是MSA的关键致病机制，指出了改善髓磷脂维持的新治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.